Morbidity and mortality associated with disease-induced ischemic trauma of the vital organs, for instance as seen in acute myocardial infarction, represent major health problems in the developed world.
Considerable biochemical, physiological and pharmacological evidence supports the occurrence and importance of oxygen free radical-induced lipid peroxidation (LPO) in cardiac ischemia/reperfusion injury (Meerson, F. Z. et al., Basic Res. Cardiol. (1982) 77, 465-485; Downey, J. M., Ann. Rev. Physiol. (1990) 52, 487-504). It has been proposed that reoxygenation of ischaemic myocardium leads to generation of O.sub.2 and H.sub.2 O.sub.2 within the tissue which can, in the presence of transition metal ions, become converted into highly-reactive hydroxyl radicals (OH) which initiate LPO, a radical chain reaction, leading to changes in cell membrane integrity and tissue injury (McCord, J. M., N. Engl. J. Med. (1985), 312, 159-163; McCord, J. M., Fed. Proc., (1987) 46, 2402; Kagan, V. E., Lipid Peroxidation in Biomembranes, (1988) CRC Press, Boca Raton Fla.). Marked activation of LPO in experimental myocardial infarction, as well as reoxygenation following transitory ischemia, have been demonstrated (Meerson et al., 1982; Rao et al., Adv. Exp. Med. Biol., (1983) 161,347-363). Exposure of myocytes or whole heart to oxidant-generating systems produced severe injury, including inactivation of the ATP-dependent Ca.sup.++ sequestering system of cardiac sarcoplasmic reticulum (Halliwell, B. and Gutteridge, J. M. C. Free Radicals in Biology and Medicine, 2d ed., (1989) Clarendon Press, Oxford, England, 442-444). A significant increase in plasma LPO levels has also been reported recently in patients with myocardial infarction, especially during the initial 48 hrs after an attack (Loeper et al., Clinica Chimica Acta, (1991) 196, 119-126). The importance of LPO and oxygen radicals in tissue damage associated with ischemia is further supported by the protective effect of natural and synthetic antioxidants such as vitamin E and the lazaroid U-74500A (Levitt, M. A., Clin. Res. (1991) 39, 265A) or antioxidant enzymes such as superoxide dismutase (SOD) and catalase in diverse ischemic models (for review see Halliwell and Gutteridge, 1989).
Given the high incidence of disease-induced ischemic trauma of the vital organs, in particular, of the cardiovascular system including the heart, e.g., together with the high survival rate of patients suffering these traumas in the developed world, there is a great need for pharmaceutical agents which prevent the occurence of such traumas as well as which protect the vital organs of patients in post-traumatic recovery from organ ischemic reperfusion injury.